This invention relates to a series of squaric acid derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.
Over the last few years it has become increasingly clear that the physical interaction of inflammatory leukocytes with each other and other cells of the body plays an important role in regulating immune and inflammatory responses [Springer, T A. Nature, 346, 425, (1990); Springer, T. A. Cell 76, 301, (1994)]. Many of these interactions are mediated by specific cell surface molecules collectively referred to as cell adhesion molecules.
The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family. This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure. At least 14 different integrin alpha chains and 8 different integrin beta chains have been identified [Sonnenberg, A. Current Topics in Microbiology and Immunology, 184, 7, (1993)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in this field. Thus the integrin termed xcex14xcex21 consists of the integrin alpha 4 chain associated with the integrin beta 1 chain, but is also widely referred to as Very Late Antigen 4 or VLA4.
Some integrin chains are capable of pairing with more than one partner. For example, the xcex1v chain has been reported to pair with the beta 1 chain, the beta 3 chain, the beta 5 chain, the beta 6 chain and the beta 8 chain to give molecules which bind to different sets of ligands and which are referred to respectively as the integrins aver xcex1vxcex21, xcex1vxcex23, xcex1vxcex25, xcex1vxcex26, and xcex1vxcex28. Not all of the potential pairings of integrin alpha and beta chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognised [Sonnenberg, A ibid].
The importance of integrin function in normal physiological responses is highlighted by two human deficiency diseases in which integrin function is defective. Thus in the disease termed Leukocyte Adhesion Deficiency (LAD) there is a defect in one of the families of integrins expressed [on leukocytes. Patients suffereing from this disease have a reduced ability to recruit leukocytes to inflammatory sites and suffer recurrent infections which in extreme cases may be fatal. In the case of patients suffering from the disease termed Glanzman""s thrombasthenia (a defect in a member of the beta 3 integer famly) there is a defect in blood clotting.
The potential to modify integrin function in such a way as to beneficially modulate cell adhesion has been extensively investigated in animal models using specific monoclonal antibodies and peptides that block various functions of these molecules [e.g. Issekutz, T. B. J. Immunol. 3394, (1992); Li, Z. et al Am. J. Physiol. 263, L723, (1992); Mitjans et al J. Cell Sci. 108, 2825 (1995), Brooks P. C. et al J. Clin. Invest. 96, 1815 (1995), Binns, R. M. et al J. Immunol. 157,4094, (1996), Hammes, H-P, et al Nature Medicine 2, 529 (1996), Srivata, S. et al Cardiovascular Res. 36, 408 (1997)]. A number of monoclonal antibodies which block integrin function are currently being investigated for their therapeutic potential in human disease.
Inhibition of integrin-mediated cell interaction can be expected to be beneficial in a number of disease states, and in addition to the monoclonal antibodies and peptides just mentioned there has been great interest in selective low molecular weight inhibitors of integrin function. Thus, for example selective xcex14 integrin inhibitors have been described in International patent Specifications Nos. WO96/22966, WO97/03094, WO 98/04247, WO98/04913, WO98/53814, WO98/53817, WO98/53818, WO98/54207, WO98/58902, WO99/06390, WO99/064310-6437, WO99/10312, WO99/10313, WO99/67230, WO 99/26922, WO99/60015, WO99/26921, WO9936393, WO99/52898 and WO99/64395. Numerous selective xcex1v integrin inhibitors have also been described, for example in International Patent Specifications Nos. WO97/08145, WO97/23480, WO97/36858, WO97136859, WO97/36861, WO97136862, WO97/44333, WO97/47618, WO98/31359, WO98/25892, WO98/18460, WO99/44994, WO99/30709, WO99/31061, WO 99/26945, WO99/52896, WO99/52879, WO99/32457, WO99/31099, WO00/07544, WO00/00486, WO00/06169, WO00/17197 and WO00/01383.
While it is clearly possible to obtain selective integrin inhibitors, their usefulnesses in medicine may be limited due to poor pharmacokinetic properties. Thus, for example, in our hands, integrin inhibitors falling within the general structural types featured in the above-mentioned patent specifications are not particularly attractive for development as medicines since they can be cleared rapidly from the body. In order to overcome this problem we have made use of a squaric acid framework which can be readily adapted to provide potent and selective integrin inhibitors using recognised integrin binding groups (for example as described herein and in the patent specifications listed above), which advantageously possess good pharmacokinetic properties, especially low plasma clearance.
Thus according to one aspect of the invention we provide a compound of formula (1) 
wherein
R1 is an integrin binding group;
R2 is a hydrogen atom or a C1-6alkyl group;
L1 is a covalent bond or a linker atom or group;
n is zero or the integer 1;
Alk1 is an optionally substituted aliphatic chain;
R3 is a hydrogen atom or an optionally substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group: and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that compounds of formula (1) may have one or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates. Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
In the compounds according to the invention, integrin-binding groups represented by R1 include for example those which are able to bind xcex14- or xcex1v-integrins. Particular examples of such integrins include xcex14xcex21, xcex14xcex27 and xcex1vxcex23 integrins.
In general, the term integrin-binding group is used herein in relation to R1 to mean any group which when part of the compound of formula (1) is able to interact with an integrin to modulate cell adhesion in vivo and achieve a therapeutic response. Typically the R1 group may bind to the integrin in such a way that it modulates the interaction of the integrin with its ligand. Thus for example the R1 group may inhibit binding of the ligand and decrease cell adhesion. Such a response enables appropriate R1 groups to be readily identified using small scale routine in vitro screening assays to determine the degree of inhibition of integrin-ligand binding in the presence of a compound of formula (1). Examples of such screening assays are widely reported in the literature, for example in the papers and International patent specifications described above, and in the Examples hereinafter.
Thus in general R1 may be any group which when present in a compound of formula (1) is able to bind to an integrin such that the compound of formula (1) inhibits the binding of the integrin with its ligand with an IC50 of 10 xcexcM or below, particularly 1 xcexcM or below, especially 500 nM or below, e.g. in the range 0.001-500 nM.
Particular R1 groups in compounds of the invention include those of formula Ar1L2Ar2Alk- wherein Ar1 is an optionally substituted aromatic or heteroaromatic group, L2 is a linker atom or group, Ar2 is an optionally substituted phenylene or nitrogen-containing six-membered heteroarylene group and Alk is a chain: 
where R is a carboxylic acid (xe2x80x94CO2H) or a derivative or biostere thereof.
R1 groups of this type are particularly useful for binding xcex14 integrins and compounds of formula (1) incorporating the Ar1L2Ar2Alk- function can be expected to inhibit xcex14 integrins such as xcex14xcex21 and/or xcex14xcex27 at concentrations at which they generally have no or minimal inhibitory action on integrins of other a subgroups. Such compounds are of use in medicine, for example in the prophylaxis and treatment of immune or inflammatory disorders as described hereinafter.
Optionally substituted aromatic groups represented by Ar1 when present in the group R1 include for example optionally substituted monocyclic or bicyclic fused ring C6-12 aromatic groups, such as phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl groups.
Optionally substituted heteroaromatic groups represented by the group Ar1 when present in the group R1 include for example optionally substituted C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example eight- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups of these types include pyrrolyl, furyl, thienyl, imidazolyl, Nxe2x80x94C1-16alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, [2,3-dihydro]benzothienyl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, especially 2,6-naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.
Each aromatic or heteroaromatic group represented by the group Ar1 may be optionally substituted on any available carbon or, when present, nitrogen atom. One, two, three or more of the same or different substituents may be present and each substituent may be selected for example from an atom or group xe2x80x94L3(Alk2)tL4(R4)u in which L3 and L4, which may be the same or different, is each a covalent bond or a linker atom or group, t is zero or the integer 1, u is an integer 1, 2 or 3, Alk2 is an aliphatic or heteroaliphatic chain and R4 is a hydrogen or halogen atom or a group selected from optionally substituted C1-6alkyl or C3-8 cycloalkyl, xe2x80x94OR5 [where R5 is a hydrogen atom, an optionally substitued C1-6alkyl or C3-8 cycloalkyl group], xe2x80x94SR5, xe2x80x94NR5R6 [where R6 is as just defined for R5 and may be the same or different], xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3H, xe2x80x94SOR5, xe2x80x94SO2R5, xe2x80x94SO3R5, xe2x80x94OCO2R5, xe2x80x94CONR5R6, xe2x80x94OCONR5R6, xe2x80x94CSNR5R6, xe2x80x94COR5, xe2x80x94OCOR5, xe2x80x94N(R5)COR6, xe2x80x94N(R5)CSR6, xe2x80x94SO2N(R5)(R6), xe2x80x94N(R5)SO2R6, N(R5)CON(R6)(R7) [where R7 is a hydrogen atom, an optionally substituted C1-6alkyl or C3-8cycloalkyl group], xe2x80x94N(R5)CSN(R6)(R7) or xe2x80x94N(R5)SO2N(R6)(R7), provided that when t is zero and each of L3 and L4 is a covalent bond then u is the integer 1 and R4 is other than a hydrogen atom.
When L3 and/or L4 is present in these substituents as a linker atom or group it may be any divalent linking atom or group. Particular examples include xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(R8)xe2x80x94 [where R8 is a hydrogen atom or an optionally substituted C1-6alkyl group], xe2x80x94N(R8)Oxe2x80x94, xe2x80x94N(R8)Nxe2x80x94, xe2x80x94CON(R8)xe2x80x94, xe2x80x94OC(O)N(R8)xe2x80x94, xe2x80x94CSN(R8)xe2x80x94, xe2x80x94N(R8)COxe2x80x94, xe2x80x94N(R8)C(O)Oxe2x80x94, xe2x80x94N(R8)CSxe2x80x94, xe2x80x94S(O)2N(R8)xe2x80x94, xe2x80x94N(R8)S(O)2xe2x80x94, xe2x80x94N(R8)CON(R8)xe2x80x94, xe2x80x94N(R8)CSN(R8)xe2x80x94, or xe2x80x94N(R8)SO2N(R8)xe2x80x94 groups. Where the linker group contains two R8 substituents, these may be the same or different.
When R4, R5, R6, R7 and/or R8 is present as a C1-6alkyl group it may be a straight or branched C1-6alkyl group, e.g. a C1-3alkyl group such as a methyl or ethyl group. C3-8cycloalkyl groups represented by R4, R5, R6, R7 and/or R8 include C3-6cycloalkyl groups e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Optional substituents which may be present on such alkyl and cycloalkyl groups include for example one, two or three substituents which may be the same or different selected from halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or hydroxy or C1-6alkoxy e.g. methoxy or ethoxy groups.
When the groups R5 and R6 or R6 and R7 are both C1-6alkyl groups these groups may be joined, together with the N atom to which they are attached, to form a heterocyclic ring. Such heterocyclic rings may be optionally interrupted by a further heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R5)xe2x80x94. Particular examples of such heterocyclic rings include piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl and piperazinyl rings.
When Alk2 is present as an aliphatic or heteroaliphatic chain it may be for example any divalent chain corresponding to the below-mentioned aliphatic or heteroaliphatic group described for Alk1 or R3 respectively.
Halogen atoms represented by R4 in the optional Ar1 substituents include fluorine, chlorine, bromine, or iodine atoms.
Examples of the substituents represented by xe2x80x94L3(Alk2)tL4(R4)u when present in Ar1 groups in compounds of the invention include atoms or groups xe2x80x94L3Alk2L4R4, xe2x80x94L3Alk2R4, xe2x80x94L3R4, xe2x80x94R4 and xe2x80x94Alk2R4 wherein L3, Alk2, L4 and R4 are as defined above. Particular examples of such substituents include xe2x80x94L3CH2L4R4, xe2x80x94L3CH(CH3)L4R4, xe2x80x94L3CH(CH2)2L4R4, xe2x80x94L3CH(CH3)R4, xe2x80x94L3(CH2)2R4, xe2x80x94CH2R4, xe2x80x94CH(CH3)R4, xe2x80x94(CH2)2R4 and xe2x80x94R4 groups.
Thus Ar1 in compounds of the invention may be optionally substituted for example by one, two, three or more halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, and/or C1-6alkyl, e.g. methyl, ethyl, n-propyl, ipropyl, n-butyl or t-butyl, C3-8cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, C1-6hydroxyalkyl, e.g. hydroxymethyl, hydroxyethyl or xe2x80x94C(OH)(CF3)2, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxy-propylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2-hydroxyethoxy, haloC1-6alkyl, e.g. xe2x80x94CF3, xe2x80x94CHF2, CH2F, haloC1-6alkoxy, e.g. xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2F, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6 dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, isopropylaminoethoxy, or dimethylaminopropoxy, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk3 [where Alk3 is as defined below for Alk7], C1-6 alkanoyl e.g. acetyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, sulphonyl (xe2x80x94SO3H), xe2x80x94SO3Alk3, C1-6alkylsulphinyl, e.g. methylsulphinyl, C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6alkylaminothiocarbonylC1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoylamino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino groups.
L2 when present as part of the group R1 in compounds of the invention may be a linker atom or group L2a or a linker -Alka(L2a)yxe2x80x94, where Alka is an optionally substituted aliphatic or heteroaliphatic chain as previously defined for Alk2, and L2a is a linker atom or group as described above for L3 and L4 and y is zero or the integer 1.
Optionally substituted nitrogen-containing six-membered heteroarylene groups represented by Ar2 when present as part of the group R1 include optionally substituted pyridiyl, pyrimidindiyl, pyridazindiyl, pyrazindiyl and triazindiyl groups. Each group may be attached to the remainder of the molecule through any available ring carbon atoms.
The phenylene and nitrogen-containing heteroarylene groups represented by Ar2 may be optionally substituted by one or two substituents selected from the atoms or groups xe2x80x94L3(Alk2)tL4(R4)u described herein. Where two of these atoms or groups are present they may be the same or different.
When the group R is present in R1 in compounds of the invention as a derivative of a carboxylic acid it may be for example a carboxylic acid ester or amide. Particular esters and amides include xe2x80x94CO2Alk7 and xe2x80x94CONR5R6 groups as defined herein. When R is a biostere of a carboxylic acid it may be for example a tetrazole or other acid such as phosphonic acid, phosphinic acid, sulphonic acid, sulphinic acid or boronic acid or an acylsulphonamide group.
When the group R2 is present in compounds of the invention as a C1-6alkyl group it may be for example a straight or branched C1-6alkyl group, e.g. a C1-3alkyl group such as a methyl or ethyl group.
The linker atom or group represented by L1 in compounds of formula (1) may be any linker atom or group as described above for the linker atom or group L3.
When the group Alk1 is present in compounds of formula (1) as an optionally substituted aliphatic chain it may be an optionally substituted C1-10 aliphatic chain. Particular examples include optionally substituted straight or branched chain C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene chains.
Particular examples of aliphatic chains represented by Alk1 include optionally substituted xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, xe2x80x94(CH2)2CH2xe2x80x94, xe2x80x94(CH2)3CH2xe2x80x94, xe2x80x94CH(CH3)(CH2)2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, xe2x80x94C(CH3)2CH2xe2x80x94xe2x80x94CH2C(CH3)2CH2xe2x80x94, xe2x80x94(CH2)2C(CH3)2CH2xe2x80x94, xe2x80x94(CH2)4CH2xe2x80x94, xe2x80x94(CH2, xe2x80x94CHCHxe2x80x94, xe2x80x94CHCHCH2xe2x80x94, xe2x80x94CH2xe2x80x94CHCHxe2x80x94, xe2x80x94CHCHCH2CH2xe2x80x94, xe2x80x94CH2CHCHCH2xe2x80x94, xe2x80x94(CH2)2CHCHxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94CCCH2xe2x80x94, xe2x80x94CH2CCxe2x80x94, xe2x80x94CCCH2CH2xe2x80x94, xe2x80x94CH2CCCH2xe2x80x94 or xe2x80x94(CH2)2CCHxe2x80x94 groups.
Heteroaliphatic groups represented by the group R3 in the compounds of formula (1) include the aliphatic chains just described for Alk1 but with each containing a terminal hydrogen atom and additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L5 where L5 is as defined above for L3 when L3 is a linker atom or group. Each L5 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group.
Particular examples include optionally substituted xe2x80x94L5CH3, xe2x80x94CH2L5CH3, xe2x80x94L5CH2CH3, xe2x80x94CH2L5CH2CH3, xe2x80x94(CH2)2L5CH3, xe2x80x94(CH2)3L5CH3, and xe2x80x94(CH2)2L5CH2CH3 groups.
The optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk1 and R3 respectively include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or xe2x80x94OH, xe2x80x94CO2H, xe2x80x94CO2R9, where R9 is an optionally substituted straight or branched C1-6alkyl group as defined above for R4, xe2x80x94CONHR9, xe2x80x94CON(Ra)2, xe2x80x94COCH3, C1-6alkoxy, e.g. methoxy or ethoxy, thiol, xe2x80x94S(O)R9, xe2x80x94S(O)2R9, C1-6alkylthio e.g. methylthio or ethylthio, amino or substituted amino groups. Substituted amino groups include xe2x80x94NHR9 and xe2x80x94N(R9)2 groups . Where two R9 groups are present in any of the above substituents these may be the same or different.
Optionally substituted cycloaliphatic groups represented by the group R3 in compounds of the invention include optionally substituted C3-10 cycloaliphatic groups. Particular examples include optionally substituted C3-10 cycloalkyl, e.g. C3-7 cycloalkyl or C3-10 cycloalkenyl, e.g C3-7 cycloalkenyl groups.
Optionally substituted heterocycloaliphatic groups represented by the group R3 include optionally substituted C3-10heterocycloaliphatic groups. Particular examples include optionally substituted C3-10heterocycloalkyl, e.g. C3-7 heterocycloalkyl, or C3-10heterocycloalkenyl, e.g. C3-7 hetercycloalkenyl groups, each of said groups containing one, two, three or four heteroatoms or heteroatom-containing groups L5 as defined above. Optionally substituted polycycloaliphatic groups represented by the group R3 include optionally substitued C7-10 bi- or tricycloalkyl or C7-10bi- or tricycloalkenyl groups. Optionally substituted polyheterocycloaliphatic groups represented by the group R3 include the optionally substituted polycycloalkyl groups just described, but with each group additionally containing one, two, three or four L5 atoms or groups.
Particular examples of cycloaliphatic, polycycloaliphatic, heterocycloaliphatic and polyheterocycloaliphatic groups represented by the group R3 include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, adamantyl, norbornyl, norbornenyl, tetrahydrofuranyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, piperidinone, 1,4-dioxanyl, morpholinyl, morpholinone, 1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, e.g. o- or p-isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or 1,3,5,-oxadiazinyl groups.
The optional substituents which may be present on the cycloaliphatic, polycycloaliphatic, heterocycloaliphatic or polyheterocycloaliphatic groups represented by the group R3 include one, two, three or more substituents each selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl or ethyl, haloC1-6alkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, optionally substituted by hydroxyl, e.g. xe2x80x94C(OH)(CF3)2, C1-6alkoxy, e.g. methoxy or ethoxy, haloC1-6alkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, C1-6alkylthio e.g. methylthio or ethylthio, or -(Alk4)vR10 groups in which Alk4 is a straight or branched C1-3alkylene chain, v is zero or an integer 1 and R10 is a xe2x80x94OH, xe2x80x94SH, xe2x80x94N(R11)2, (in which R11 is an atom or group as defined herein for R8)xe2x80x94CN, xe2x80x94CO2R11, xe2x80x94NO2, xe2x80x94CON(R11)2, xe2x80x94CSN(R11)2, xe2x80x94COR11, xe2x80x94CSN(R11)2, xe2x80x94N(R11)COR11, xe2x80x94N(R11)CSR11, xe2x80x94SO2N(R11)2, xe2x80x94N(R11)SO2R11, xe2x80x94N(R11)CON(R11)2, xe2x80x94N(R11)CSN(R11)2, N(R11)SO2N(R11)2 or optionally substituted phenyl group. Where two R11 atoms or groups are present in these substituents these may be the same or different. Optionally substituted phenyl groups include phenyl substituted by one, two or three of the R13 groups described below.
Additionally, when the group R3 is a heterocycloaliphatic group containing one or more nitrogen atoms each nitrogen atom may be optionally substituted by a group xe2x80x94(L6)p(Alk5)qR12 in which L6 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CON(R11)xe2x80x94, xe2x80x94CSN(R11)xe2x80x94 or SO2N(R11)xe2x80x94; p is zero or an integer 1; Alk5 is an optionally substituted aliphatic or heteroaliphatic chain; q is zero or an integer 1; and R12 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group.
Optionally substituted aliphatic or heteroaliphatic chains represented by Alk5 include those optionally substituted chains described above for Alk1 and R3 respectively.
Cycloaliphatic, heterocycloaliphatic, polycycloaliphatic or polyheterocycloaliphatic groups represented by R12 include those groups just described for the group R3. Optional substituents which may be present on these groups include those described above in relation to Alk1 and R3 aliphatic and heteroaliphatic chains.
When the group R3 is an optionally substituted aromatic or heteroaromatic group it may be for example an aromatic or heteroaromatic group as described herein for the group Ar1.
Optional substituents which may be present on the aromatic or heteroaromatic groups represented by the group R3 include one, two, three or more substituents, each selected from an atom or group R13 in which R13 is R13a or -Alk6(R13a)m, where R13a is a halogen atom, or an amino (xe2x80x94NH2), substituted amino, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), substituted hydroxyl, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), substituted thiol, xe2x80x94COR14 [where R14 is an -Alk6(R13a)m, cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group], xe2x80x94CSR14, xe2x80x94SO3H, xe2x80x94SOR14, xe2x80x94SO2R14, xe2x80x94SO3R14, xe2x80x94SO2NH2, xe2x80x94SO2NHR14 SO2N(R14)2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR14, xe2x80x94CSNHR14, xe2x80x94CON[R14]2, xe2x80x94CSN(R14)2, xe2x80x94N(R11)SO2R14, xe2x80x94N(SO2R14)2, xe2x80x94NH(R11)SO2NH2, xe2x80x94N(R11)SO2NHR14, xe2x80x94N(R11)SO2N(R14)2, xe2x80x94N(R11)COR14, xe2x80x94N(R11)CONH2, xe2x80x94N(R11)CONHR14, xe2x80x94N(R11)CON(R14)2, xe2x80x94N(R11)CSNH2, xe2x80x94N(R11)CSNHR14, xe2x80x94N(R11)CSN(R14)2, xe2x80x94N(R11)CSR14, xe2x80x94N(R11)C(O)OR14, xe2x80x94SO2NHet1 (where xe2x80x94NHet1 is an optionally substituted C5-7cyclicamino group optionally containing one or more other xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R11)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, S(O) or xe2x80x94S(O)2 groups], xe2x80x94CONHet1, xe2x80x94CSNHet1, xe2x80x94N(R11)SO2NHet1, xe2x80x94N(R11)CONHet1, xe2x80x94N(R11)CSNHet1, xe2x80x94SO2N(R11)Het2 [where Het2 is an optionally substituted monocyclic C5-7carbocyclic group optionally containing one or more xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R11)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 groups], xe2x80x94Het2, xe2x80x94CON(R11)Het2, xe2x80x94CSN(R11)Het2, xe2x80x94N(R11)CON(R11)Het2, xe2x80x94N(R11)CSN(R11)Het2, cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group; Alk6 is a straight or branched C1-6alkylene, C2-6alkenylene or C2-6alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94S(O)n [where n is an integer 1 or 2] or xe2x80x94N(R15)xe2x80x94 groups [where R15 is a hydrogen atom or C1-6alkyl, e.g. methyl or ethyl group]; and m is zero or an integer 1, 2 or 3. It will be appreciated that when two R11 or R14 groups are present in one of the above substituents, the R11 or R14 groups may be the same or different.
When in the group -Alk6(R13a)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R13a may be present on any suitable carbon atom in -Alk6. Where more than one R13a substituent is present these may be the same or different and may be present on the same or different atom in -Alk6. Clearly, when m is zero and no substituent R13a is present the alkylene, alkenylene or alkynylene chain represented by Alk6 becomes an alkyl, alkenyl or alkynyl group.
When R13a is a substituted amino group it may be for example a group xe2x80x94NHR14 [where R14 is as defined above] or a group xe2x80x94N(R14)2 wherein each R14 group is the same or different.
When R13a is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R13a is a substituted hydroxyl or substituted thiol group it may be for example a group xe2x80x94OR14 or a xe2x80x94SR14 or xe2x80x94SC(xe2x95x90NH)NH2 group respectively.
Esterified carboxyl groups represented by the group R13a include groups of formula xe2x80x94CO2Alk7 wherein Alk7 is a straight or branched, optionally substituted C1-8alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group; a C1-12arylC1-8alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-12aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-12aryloxyC1-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group; an optionally substituted C1-8alkanoyloxyC1-8alkyl group, such as a pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; or a C6-12aroyloxyC1-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group. Optional substituents present on the Alk7 group include R13a substituents described above.
When Alk6 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R9)xe2x80x94 groups.
Cycloaliphatic or heterocycloaliphatic groups represented by the groups R13a or R14 include those optionally substituted C3-10cycloaliphatic or C3-10heterocycloaliphatic groups described above for R3.
Aryl or heteroaryl groups represented by the groups R13a or R14 include mono- or bicyclic optionally substituted C6-12 aromatic or C1-9 heteroaromatic groups as described above for the group Ar1. The aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
When xe2x80x94NHet1 or xe2x80x94Het2 forms part of a substituent R13 each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on xe2x80x94NHet1 or xe2x80x94Het2 include those R7 substituents described above.
Particularly useful atoms or groups represented by R13 include fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl, piperazinyl, e.g. t-butyloxycarbonylpiperazinyl, pyrrolidinyl, dioxolanyl, dioxanyl, oxazolidinyl, thiazolidinyl, imidazolidinyl or piperidinyl, C1-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C4-7cycloalkyl, e.g. cyclobutyl, cyclopentyl, C5-7cycloalkoxy, e.g. cyclopentyloxy, haloC1-6alkyl, e.g. trifluoromethyl, haloC1-6alkoxy, e.g. trifluoromethoxy, C1-6alkylamino, e.g. methylamino, ethylamino or propylamino, C6-12arylC1-6alkylamino, e.g. benzylamino, 4-fluorobenzylamino or 4-hydroxyphenylethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, aminoC1-6alkylamino, e.g. aminoethylamino or aminopropylamino, optionally substituted Het1NC1-6alkylamino, e.g. 3-morpholinopropylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy, hydroxyC1-6alkylamino, e.g. 2-hydroxyethylamino, 3-hydroxypropylamino or 3-hydroxybutylamino, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk7 [where Alk7 is as defined above], C1-6 alkanoyl e.g. acetyl, propyryl or butyryl, optionally substituted benzoyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, xe2x80x94SC(xe2x95x90NH)NH2, sulphonyl (xe2x80x94SO3H), xe2x80x94SO3Alk7, C1-6alkylsulphinyl, e.g. methylsulphinyl, ethylsulphinyl or propylsulphinyl, C1-6alkylsulphonyl, e.g. methylsulphonyl, ethylsulphonyl or propylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl, ethylaminosulphonyl or propylaminosulphonyl C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl, ethylaminocarbonyl or propylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6alkylaminoC1-6alkylaminocarbonyl, e.g. methylaminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6alkylaminothiocarbonyl C1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, xe2x80x94CONHC(xe2x95x90NH)NH2, C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, haloC1-6alkylsulphonylamino, e.g. trifluoromethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylC1-6alkylamino, optionally substituted phenylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, amino1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoylamino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino, benzyloxycarbonylaminoC1-6alkyl e.g. benzyloxycarbonylaminoethyl, thiobenzyl, pyridylmethylthio or thiazolylmethylthio groups.
Where desired, two R13 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6alkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R13 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group represented by R3.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
In the compounds according to the invention the group R1 is preferably an Ar1L2Ar2Alk- group. In compounds of this type Ar1 is preferably an optionally substituted phenyl, monocyclic heteroaromatic or bicyclic heteroaromatic group. Particularly useful monocyclic heteroaromatic groups are optionally substituted five- or six-membered heteroaromatic groups as described previously, especially five- or six-membered heteroaromatic groups containing one or two heteroatoms selected from oxygen, sulphur or nitrogen atoms. Nitrogen-containing groups are especially useful, particularly pyridyl or pyrimidinyl groups. Particularly useful substituents present on these Ar1 groups include halogen atoms or optionally substituted alkyl, xe2x80x94OR5, xe2x80x94SR5, xe2x80x94NR5R6, xe2x80x94CO2H, xe2x80x94CO2CH3, xe2x80x94NO2 or xe2x80x94CN groups as described above in relation to the compounds of formula (1). Particularly useful bicyclic heteroaromatic groups represented by Ar1 include optionally substituted ten-membered fused-ring heteroaromatic groups containing one or two heteroatoms, especially nitrogen atoms. Particular examples include optionally substituted naphthyridinyl, especially 2,6-naphthyridinyl, quinolinyl and isoquinolinyl, especially isoquinolin-1-yl groups. Particular optional substituents include those just described for monocyclic heteroaromatic groups.
A particularly useful group of compounds according to the invention has the formula (2a): 
wherein xe2x80x94Wxe2x95x90 is xe2x80x94CHxe2x95x90 or xe2x80x94Nxe2x95x90;
R16 and R17, which may be the same or different is each a hydrogen atom or an atom or group xe2x80x94L3(Alk2)tL4(R4)u in which L3, Alk2, t, L4 R4 and u are as defined previously;
L1, L2, Ar2, Alk, R2, Alk1, n and R3 are as defined for formula (1);
and the salts, solvates, hydrates and N-oxides thereof.
xe2x80x94Wxe2x95x90 in compounds of formula (2a) is preferably xe2x80x94Nxe2x95x90.
R16 and R17 in compounds of formula (2a) is each preferably as particularly described above for compounds of formula (1), other than a hydrogen atom. Particularly useful R16 and R17 substituents include halogen atoms, especially fluorine or chlorine atoms, or methyl, halomethyl, especially xe2x80x94CF3, xe2x80x94CHF2 or xe2x80x94CH2F, methoxy or halomethoxy, especially xe2x80x94OCF3, xe2x80x94OCHF2 or xe2x80x94OCH2F groups.
A further particularly useful group of compounds according to the invention has the formula (2b): 
wherein
R16, L1, L2, Ar2, Alk, R2, Alk1, n and R3 are as defined for formula (2a);
g is zero or the integer 1, 2, 3 or 4;
and the salts, solvates, hydrates and N-oxides thereof.
Each R16 atom or group in compounds of formula (2b) may be independently selected from an atom or group xe2x80x94L3(Alk2)tL3(R4)u in which L3, Alk2, t, L4, R4 and u are as previously defined. Particularly useful R16 substituents when present in compounds of formula (2b) include halogen atoms, especially fluorine, chlorine or bromine atoms, or methyl, halomethyl, especially xe2x80x94CF3, methoxy or halomethoxy, especially xe2x80x94OCF3, xe2x80x94CN, xe2x80x94CO2Me, xe2x80x94NO2, amino (xe2x80x94NH2), substituted amino (xe2x80x94NR5R6) and xe2x80x94N(R5)COCH3, especially xe2x80x94NHCOCH3 groups.
In one preferred group of compounds of formula (2b) each R16 is a hydrogen atom.
Another particularly useful group of compounds according to the invention has the formula (2c): 
wherein R16, g, L1, L2, Ar2, Alk, R2, Alk1, n and R3 are as defined for formula (2b);
and the carbon atoms at positions 6 and 7 of the naphthyridine ring are indicated with the appropriate numerals,
and the salts, solvates, hydrates and N-oxides thereof.
Each R16 atom or group in compounds of formula (2c) may be independently selected for an atom or group xe2x80x94L3(Alk2)tL4(R4)u in which L3, Alk2, t, L4, R4 and u areas previously defined. Particularly useful R16 substituents when present in compounds of formula (2c) include halogen atoms, especially fluorine or chlorine atoms, methyl, halomethyl, especially xe2x80x94CF3, methoxy or halomethoxy, especially xe2x80x94OCF3, xe2x80x94CN, xe2x80x94CO2Me, xe2x80x94NO2, amino (xe2x80x94NH2), substituted amino (xe2x80x94NR5R6) and xe2x80x94N(R5)COCH3, especially xe2x80x94NHCOCH3 groups.
In one preferred group of compounds of formula (2c) g is the integer 1 and R16 is a methoxy group, especially a methoxy group present at the 6-position. In another preferred group of compounds of formula (2c) g is the integer 2 and each R16 group is a methoxy group, especially a methoxy group present at the 6- and 7-positions.
Alk in compounds of the invention is preferably: 
or, especially, xe2x80x94CH2CH(R)xe2x80x94.
R in the compounds of formulae (1), (2a), (2b) and (2c) is preferably a xe2x80x94CO2H group.
In general in compounds of formulae (1), (2a), (2b) and (2c) R2 is preferably a hydrogen atom.
In general in compounds of formula (2a) L2 is preferably L2 where L2a is a xe2x80x94CON(R8)xe2x80x94 group, especially xe2x80x94CONHxe2x80x94.
In general in compounds of formulae (2b) and (2c) L2 is preferably L2a where L2a is an xe2x80x94Oxe2x80x94 atom or xe2x80x94N(R8)xe2x80x94 group. An especially useful xe2x80x94N(R8)xe2x80x94 group is xe2x80x94NHxe2x80x94.
The group Ar2 in compounds of formulae (1), (2a), (2b) and (2c) is preferably an optionally substituted phenylene group. Particularly useful groups include optionally substituted 1,4-phenylene groups.
In general in compounds of formulae (1), (2a), (2b) and (2c) when n is zero or the integer 1 the group R3 may especially be a hydrogen atom or an optionally substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group as defined herein. Particularly useful groups of this type include optionally substituted C2-6heteroalkyl, particularly C1-3alkoxyC1-3alkyl, especially methoxypropyl, optionally substituted C3-7cycloalkyl, especially optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl or cyclohexyl, optionally substituted C5-7heterocycloaliphatic, especially optionally substituted pyrrolidinyl, piperidinyl or thiazolidinyl, especially optionally substituted phenyl and optionally substituted C5-7heteroaromatic, especially optionally substituted pyridyl, pyrimidinyl or triazinyl groups. Optional substituents on these groups include in particular R13 atoms or groups where the group is an aromatic or heteroaromatic group and halogen atoms or C1-6alkyl, especially methyl, haloC1-6alkyl, especially trifluoromethyl, C1-6alkoxy, especially methoxy, haloC1-6alkoxy, especially trifluoromethoxy or xe2x80x94(L6)p(Alk5)qR12 groups as described earlier where the group is a nitrogen-containing heterocycloaliphatic group such as a pyrrolidinyl, piperidinyl or thiazolidinyl group. Particularly useful xe2x80x94(L6)p(Alk5)qR12 groups include those in which L6 is a xe2x80x94COxe2x80x94 group. Alk5 in these groups is preferably present (i.e. q is preferably an integer 1) and in particular is a xe2x80x94CH2xe2x80x94 chain.
Compounds of this type in which R12 is a hydrogen atom or an optionally substituted aromatic or heteroaromatic group, especially an optionally substituted phenyl, pyridyl or imidazolyl group are particularly preferred.
In one preferred class of compounds of formulae (1), (2a), (2b) and (2c) L1 is present as a xe2x80x94N(R8)xe2x80x94 group. Particularly useful xe2x80x94N(R8)xe2x80x94 groups include xe2x80x94NHxe2x80x94, xe2x80x94N(CH3)xe2x80x94, xe2x80x94N(CH2CH3)xe2x80x94 and xe2x80x94N(CH2CH2CH3)xe2x80x94 groups. In this class of compounds n is preferably the integer 1 and Alk1 is preferably an optionally substituted straight or branched C1-6alkylene chain. Particularly useful Alk1 chains include xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94 and xe2x80x94C(CH3)2CH2xe2x80x94. R3 in this class of compounds is preferably a hydrogen atom.
In another preferred class of compounds of formulae (1), (2a), (2b) and (2c) L1 is a covalent bond, n is the integer 1 and Alk1 is an optionally substituted straight or branched C1-6alkylene chain. Particularly useful Alk1 chains include optionally substituted xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH(CH3)CH2xe2x80x94 and especially xe2x80x94C(CH3)2CH2xe2x80x94 chains. R3 in this class of compounds is preferably a hydrogen atom. A most especially useful optionally substituted Alk1R3 group is xe2x80x94C(CH3)3.
In another preferred class of compounds of formulae (1), (2a), (2b) and (2c), L1 is a covalent bond, n is zero and R3 is an optionally substituted C5-7heterocycloaliphatic, especially an optionally substituted piperidinyl group. A most especially useful optionally substituted piperidinyl group is an optionally substituted piperidin-1-yl group.
Particularly useful compounds of the invention include:
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-propylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl]-2-(2-t-butyl-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-{4-[(6,7-Dimethoxy-4-quinazolinyl)amino]phenyl}-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([6,7-Dimethoxy-4-quinazolinyl)oxy]phenyl]-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([6,7-Methoxy-4-quinazolinyl]amino)phenyl]-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N,N-dipropylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([2,6-Naphthyridin-1-yl]oxy)phenyl]-2-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-piperidin-1-yl-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(R)-3-{4-(3,5-Dichloro-4-pyridylcarboxamido)phenyl}-3-[(2-N,N-diethylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([2,6-Naphthyridin-1-yl]oxy)phenyl]-2-[(2-N,N-dipropylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-([2,6-Naphthyridin-1-yl]amino)phenyl]-2-[(2-N-ethyl-N-isopropylamino-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
and the salts, solvates, hydrates and N-oxides thereof.
The compounds according to the invention are generally of use in modulating cell adhesion. Thus for example when R1 in compounds of the invention is an a4-integrin binding groups the compounds are of use in the prophylaxis and treatment of diseases or disorders involving inflammation in which the extravasation of leukocytes plays a role.
Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis vasculitis or polydermatomyositis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
In another example when R1 is an xcex1V-integrin binding group the compounds may be of use in the prophylaxis and treatment of diseases or disorders involving inappropriate growth or migration of cells. Particular diseases include inflammatory diseases, and diseases involving angiogenesis, bone resorption or cllular or matrix over-expression.
Particular uses to which these compounds of the invention may be put include the treatment or inhibition of tumour growth and metastasis; retinopathy; macular degeration psoriasis; rheumatoid arthritis, osteoporosis; bone resorption following or due to joint replacement, hypercalcemia or malignancy, Paget""s disease, glucocorticoid treatment, immonilisation-induced osteopenia, hyperparathyroidism or peridontal disease, vascuar restenosis, atherosclerosis; inflammatory bowel disease; and psoriasis.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. For particle mediated administration the compounds of formula (1) may be coated on particles such as microscopic gold particles.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 100 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols Ar1, Ar2, Alk, R1, R2, R3, L1, L2, Alk1 and n when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1991]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. For convenience the processes described below all refer to a preparation of a compound of formula (1) but clearly the description applies equally to the preparation of compounds of formula (2).
Thus according to a further aspect of the invention, a compound of formula (1) in which R is a xe2x80x94CO2H group may be obtained by hydrolysis of an ester of formula (3): 
[where Ry is an alkyl group for example a C1-6alkyl group]
The hydrolysis may be performed using either an acid or a base depending on the nature of Ry, for example an organic acid such as trifluoroacetic acid or an inorganic base such as lithium, sodium or potassium hydroxide optionally in an aqueous organic solvent such as an amide e.g. a substituted amide such as dimethylformamide, an ether e.g. a cyclic ether such as tetrahydrofuran or dioxane or an alcohol e.g. methanol at a temperature from ambient to the reflux temperature. Where desired, mixtures of such solvents may be used.
According to a further aspect of the invention a compound of formula (1) may be prepared by displacement of a leaving group from a compound of formula (4): 
where Ra is a leaving group, with an amine R1R2NH or a salt thereof. Suitable leaving groups represented by Ra include halogen atoms, especially chlorine and bromine atoms, or alkoxy, e.g. methoxy, ethoxy or isopropoxy, aryloxy, e.g. dinitrophenyloxy, or aralkoxy, e.g. benzyloxy, groups.
The reaction may be performed in an inert solvent or mixture of solvents, for example a substituted amide such as dimethylformamide, an alcohol such as ethanol and/or a halogenated hydrocarbon such as dichloromethane, at a temperature from 0xc2x0 C. to the reflux temperature. Where necessary, for example when a salt of an amine R1R2NH is used, an organic base such as diisopropylethylamine can be added.
Any carboxylic acid group present in the intermediate of formula (4) or the amine R1R2NH may need to be protected during the displacement reaction, for example as an ethyl ester. The desired acid may then be obtained through subsequent hydrolysis, for example as particularly described above and generally described below.
It will be appreciated that the displacement reaction may also be performed on a compound of formula (5): 
where Rb is a leaving group as defined for Ra using an intermediate R3(Alk1)nL1H where xe2x80x94L1H is a functional group such as an amine (xe2x80x94NH2) using the reaction conditions just described.
Where desired the displacement reaction may also be performed on an intermediate of formulae (4) or (5), R1R2NH or R3(Alk1)nL1H which is linked, for example via its R1 or R3 group, to a solid support, such as a polystyrene resin. After the reaction the desired compound of formula (1) may be displaced from the support by any convenient method, depending on the original linkage chosen.
Intermediates of formulae (4) and (5) are either readily available or may be prepared from an intermediate of formula (6): 
where Ra and Rb are as previously defined and an amine R1R2NH or intermediate (R3(Alk1)nL1H by displacement as just described for the preparation of compounds of formula (1).
Intermediates of formulae R1R2NH and R3(Alk1)nL1H may be obtained from simpler, known compounds by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of formulae (1) and (2) where appropriate functional groups exist in these compounds.
Thus compounds of the invention and intermediates thereto may be prepared by alkylation, arylation or heteroarylation. For example, compounds containing a xe2x80x94L1H or xe2x80x94L2H group (where L1 and L2 is each a linker atom or group) may be treated with a coupling agent R3(Alk1)nX1 or Ar1X1 respectively in which X1 is a leaving atom or group such as a halogen atom, e.g. a fluorine, bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g. p-toluene-sulphonyloxy group.
The reaction may be carried out in the presence of a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, or an organic amine e.g. triethylamine or N,N-diisopropylethylamine or a cyclic amine, such as N-methylmorpholine or pyridine, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran.
Intermediates of formula Ar1X1 and R3(Alk1)nX1 are generally known, readily available compounds or may be prepared from known compounds by standard substitution and other synthetic procedures, for example as described herein. Thus for example compounds of formula Ar1X1 in which, for example, Ar1 represents a 2,6-naphthyridine group may be prepared from alcohols of formula Ar1OH by reaction with a halogenating agent, for example a phosphorous oxyhalide such as phosphorous oxychloride at an elevated temperature e.g. 110xc2x0 C.
Intermediate alcohols of formula Ar1OH in which, for example, Ar1 represents a 2,6-naphthyridine group may be prepared by methods well known to a person skilled in the art, e.g. by the method of Sakamoto,T. et al [Chem. Pharm. Bull. 33, 626-633, (1985)].
Alternatively alkylating agents of formula Ar1X1 in which, for example, Ar1 represents a 2,6-naphthyridine group may be prepared by reaction of a 2,6-naphthyridine N-oxide or N,Nxe2x80x2-dioxide with a halogenating agent, e.g. a phosphorous oxyhalide such as phosphorous oxychloride to give a 1-halo or 1,5-dihalo-2,6-napthyridine respectively. In the case of 1,5-dihalo-2,6-napthyridines each halogen atom may be substituted separately by a reagent such as HL2Ar2AlkN(R2)H or HL3(Alk2)tL4(R4)u by the particular methods just described above.
2,6-Napthyridine N-oxides and N,Nxe2x80x2-dioxides may be generated from the corresponding 2,6-napthyridines group by the general methods of synthesis of N-oxides described below or they may be synthesised by the methods of Numata, A. et al (Synthesis, 1999, 306-311).
Further alkylating agents of formula Ar1X1 in which, for example, Ar1 represents a 2,6-naphthyridine, may be prepared by the methods of Giacomello G. et al (Tetrahedron Letters 1965, 1117-1121), Tan, R. and Taurins, A. (Tetrahedron Letters 1965, 2737-2744), Ames, D. E. and Dodds, W. D. (J. Chem. Soc. Perkin 1 1972, 705-710) and Alhaique, F. et al (Tetdrahedron Letters, 1975, 173-174).
In a further example intermediates of formula R1R2NH may be obtained by reaction of a compound of formula Ar1L2H with a compound of formula X1Ar2AlkN(R2)H under the reaction conditions just described
Compounds of formula Ar1L2H in which, for example Ar1 represents a 2,6-naphthyridine and L2 is a xe2x80x94N(R8)xe2x80x94 group, may be prepared from substituted 4-cyano-3-cyanomethylpyridines by the methods of Alhaique, F. et al (ibid and Gazz. Chim. Ital. 1975, 105, 1001-1009) or from 3-fomylpyridines by the methods of Molina, P. at al (Tetrahedron 1992, 48, 4601-4616).
In another example, compounds containing a xe2x80x94L1 H or xe2x80x94L2H or group as defined above may be functionalised by acylation or thioacylation, for example by reaction with one of the alkylating agents just described but in which X1 is replaced by a xe2x80x94C(O)X2, C(S)X2, xe2x80x94N(R8)COX2or xe2x80x94N(R8)C(S)X2 group in which X2 is a leaving atom or group as described for X1. The reaction may be performed in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g. triethylamine or N-methylmorpholine, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride or an amide, e.g. dimethylformamide, at for example ambient temperature. Alternatively, the acylation may be carried out under the same conditions with an acid (for example one of the alkylating agents described above in which X1 is replaced by a xe2x80x94CO2H group) in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,Nxe2x80x2-dicyclohexylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxybenzotriazole. Alternatively the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to the desired acylation reaction.
In a further example compounds may be obtained by sulphonylation of a compound containing an xe2x80x94OH group by reaction with one of the above alkylating agents but in which X1 is replaced by a xe2x80x94S(O)Hal or xe2x80x94SO2Hal group in which Hal is a halogen atom such as chlorine atom] in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
In another example, compounds containing a xe2x80x94L1H or xe2x80x94L2H group as defined above may be coupled with one of the alkylation agents just described but in which X1 is replaced by an xe2x80x94OH group in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl, diisopropyl- or dimethylazodicarboxylate.
In a further example, ester groups xe2x80x94CO2R5, xe2x80x94CO2Alk3 or xe2x80x94CO2Alk7 in the compounds may be converted to the corresponding acid [xe2x80x94CO2H] by acid- or base-catalysed hydrolysis depending on the nature of the groups R5, Alk3 or Alk7. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
In a further example, xe2x80x94OR5 or xe2x80x94OR14 groups [where R5 or R14 each represents an alkyl group such as methyl group] in compounds of formula (1) may be cleaved to the corresponding alcohol xe2x80x94OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around xe2x88x9278xc2x0 C.
Alcohol [xe2x80x94OH] groups may also be obtained by hydrogenation of a corresponding xe2x80x94OCH2R14 group (where R14 is an aryl group) using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature. In another example, xe2x80x94OH groups may be generated from the corresponding ester [CO2Alk5 or CO2R5] or aldehyde [xe2x80x94CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
In another example, alcohol xe2x80x94OH groups in the compounds may be converted to a corresponding xe2x80x94OR5 or xe2x80x94OR14 group by coupling with a reagent R5OH or R14OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [xe2x80x94NHSO2NHR3 or xe2x80x94NHSO2NHAr1] groups in the compounds may be obtained, in another example, by reaction of a corresponding amine [xe2x80x94NH2] with a sulphamide R3NHSO2NH2 or Ar1NHSO2NH2 in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In another example compounds containing a xe2x80x94NHCSAr1, xe2x80x94CSNHAr1, xe2x80x94NHCSR3 or xe2x80x94CSNHR3 may be prepared by treating a corrsponding compound containing a xe2x80x94NHCOAra, xe2x80x94CONHAr1, xe2x80x94NHCOR3 or xe2x80x94CONHR3 group with a thiation reagent, such as Lawesson""s Reagent, in an anhydrous solvent, for example a cyclic ether such as tetrahydrofuran, at an elevated temperature such as the reflux temperature.
In a further example amine (xe2x80x94NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amine [xe2x80x94NH2] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [xe2x80x94NO2] group may be reduced to an amine [xe2x80x94NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around xe2x88x9278xc2x0 C., in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
In another example, sulphur atoms in the compounds, for example when present in a linker group L1 or L2 may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
In another example compounds of formula Ar1X1 (where X1 is a halogen atom such as a chlorine, bromine or iodine atom) may be converted to such compounds as Ar1CO2R20 (in which R20 is an optionally substituted alkyl, aryl or heteroaryl group), Ar1CHO, Ar1CHCHR20, Ar1CCR20, Ar1N(R20)H, Ar1N(R20)2, for use in the synthesis of for example compounds of formula R1R2NH, using such well known and commonly used palladium mediated reaction conditions as are to be found in the general reference texts Encyclopedia of Reagents for Organic Synthesis, Editor-in Chief Paquette, L. A., John Wiley and Sons, 1995 and Comprehensive Organic Functional Group Transformations, Editors-in-Chief Katritzky, A. R. et al, Pergamon, 1995.
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70xc2x0 C. to 80xc2x0 C., or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) with an appropriate base in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula (1) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
In another resolution process a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
The following Examples illustrate the invention. All temperatures are in xc2x0C. The following abbreviations are used:
NMMxe2x80x94N-methylmorpholine;
MeOHxe2x80x94methanol;
DCMxe2x80x94dichloromethane;
DIPEAxe2x80x94diisopropylethylamine;
Pyrxe2x80x94pyridine;
DMSOxe2x80x94dimethylsulphoxide;
Et2Oxe2x80x94diethylether;
EtOAcxe2x80x94ethyl acetate;
BOCxe2x80x94butoxycarbonyl;
AcOHxe2x80x94acetic acid;
EtOHxe2x80x94ethanol,
Arxe2x80x94aryl;
iPrxe2x80x94isopropyl;
Mexe2x80x94methyl;
THFxe2x80x94tetrahydrofuran,
FMOCxe2x80x949-fluorenylmethoxycarbonyl;
obsxe2x80x94obscured;
dilxe2x80x94dilute;
Buxe2x80x94butyl;
DMFxe2x80x94N,N-dimethylformamide;
brxe2x80x94broad;
appxe2x80x94apparent;
RTxe2x80x94room temperature;
DIPEAxe2x80x94diisopropylethylamine
All NMR""s were obtained at 300 mHz.
A solution of 3,5-dichloropyridine (5.00 g, 33.8 mmol) in THF (25 ml) was added to a solution of LDA [generated from nBuLi (2.5M solution in hexanes, 14.9 ml, 37.2 mmol) and diisopropylamine (4.10 g, 5.7 ml, 40.6 mmol)] in THF (25 ml) at xe2x88x9278xc2x0 under nitrogen, to give a yellow/brown slurry. The reaction was stirred for 30 min at xe2x88x9278xc2x0 then CO2 gas was bubbled through to give a clear brown solution that slowly gave a precipitate, warmed to RT over 2 h, then quenched with water (20 ml) and partitioned between Et2O (100 ml) and 1M NaOH (100 ml). The aqueous layer was separated and acidified to pH1 with concentrated hydrochloric acid and then extracted with 10% MeOH in DCM (100 mlxc3x973). The combined organic layers were dried (MgSO4) and the solvent removed under vacuum to give a brown solid that was recrystallised from ethanol and dried under vacuum to give the title compound as pinkish crystals (2.63 g, 41%). xcex4H (DMSO-d6) 8.74 (2H, s). xcex4C (DMSO-d6) 163.5, 147.7, 141.0, 126.7.
A slurry of the compound of Intermediate 1 (51.2 g, 0.267 mol) in DCM (195 ml) and thionyl chloride (195 ml, 2.67 mol) was treated with DMF (5 drops) and heated to reflux for 4 h. The reaction was concentrated in vacuo and azeotroped with toluene (2xc3x9750 ml) to give a yellow solid which was used without further purification. A solution of ethyl-(S)-3-(4-aminophenyl)-2-(t-butoxycarbonyl amino)propionate (130.8 g, 0.425 mol) in DCM (800 ml) was cooled to 0xc2x0 and treated with NMM (56.0 ml, 0.51 mol), stirred 5 minutes and then a solution of the acid chloride (98.3 g, 0.468 mol) in DCM (200 ml) was added dropwise keeping the reaction temperature below 5xc2x0. The reaction was stirred for 1 h, quenched with NaHCO3 solution (500 ml), the organic layer separated, washed with NaHCO3 solution (500 ml), 10% citric acid solution (500 ml) and NaHCO3 solution (500 ml), dried (MgSO4)and concentrated in vacuo to give a yellow solid which was recrystallised (EtOAc/hexane) to give the title compound, 140 g, 69%. xcex4H (DMSO d6), 8.8 (2H, s), 7.55 (2H, d, J 8.5 Hz), 7.23 (2H, d, J 8.5 Hz), 4.0 (3H, m), 3.4 (2H, b s), 2.9 (1H, m), 2.8 (1H, m), 1.3 (9H, s), 1.25 (3H, t). m/z (ES+, 70V) 504 (MNa+).
A solution of the compound of Intermediate 2 (70 g, 0.146 mol) in EtOAc (500 ml) and 1,4-dioxan (50 ml) was treated with a solution of HCl in EtOAc (500 ml, 3M), and stirred at RT for 4 h. The reaction was concentrated in vacuo to give a yellow solid which was triturated with Et2O then recrystallised (EtOAc/hexane) to give the title compound (59.3 g, 92%). xcex4H (DMSO d6), 11.10 (1H, s), 8.70 (2H, s), 7.55 (2H, d, J 8.4 Hz), 7.25 (2H, d, J 8.4 Hz), 4.10 (3H, m), 3.10 (2H, m), 1.10 (3H, m). m/z (ES+, 70V) 382 (MH+).
tert-Butyl lithium (2.29 ml of a 1.7M solution in pentane, 3.9 mmol) was added to a solution of 3,4-diisopropoxy-3-cyclobutene-1,2-dione (594 mg, 3 mmol) in THF (30 ml) at xe2x88x9278xc2x0 C. After 5 h trifluoroactic anhydride (636 xcexcl, 4.5 mmol) was added and stirring continued at xe2x88x9278xc2x0 C. for 30 min. The cold mixture was poured into NH4Cl(aq), extraced with EtOAc, dried (Na2SO4) and evaporated in vacuo. Column chromatography (SiO2; EtOAc/hexane, 15:85) gave the title compound as a mobile yellow oil (408 mg, 69%). xcex4H (CDCl3) 5.43 (1H, sept, J 6.2 Hz), 1.45 (6H, d, J 6.2 Hz) and 1.33 (9H, s); m/z (ES+, 70V) 197 (M++H).
1-Hydroxy-2,6-naphthyridine (550 mg) [prepared according to the method of Sakamoto, T. et al Chem. Pharm. Bull. 33, 626, (1985)] was stirred with phosphorous oxychloride (10 ml) at 110xc2x0 for 5 h. The volatiles were removed in vacuo and the residue treated carefully with ice. After diluting with water (to xcx9c25 ml), solid NaHCO3 was added to neutralise and the product extracted into EtOAc (2xc3x9780 ml). The combined organic extracts were dried (MgSO4), evaporated in vacuo, and the crude product chromatographed (SiO2; EtOAc) affording the title compound as a slightly yellow solid (420 mg, 68%). xcex4H (CDCl3) 9.35 (1H, s), 8.82 (1H, d, J 5.9 Hz), 8.48 (1H, d, J 5.6 Hz), 8.00 (1H, d, J 5.9 Hz), 7.74 (1H, d, J 5.6 Hz); m/z (ES+, 70V) 165 and 167 (MH+).
Ethyl (S)-3-(4-aminophenyl)-2-[N-(t-butyloxycarbonyl)amino]propanoate (600 mg, 1.95 mmol), Intermediate 5 (350 mg, 2.13 mmol) and DIPEA (276 mg, 372 xcexcl, 2.13 mmol) in 2-ethoxyethanol (0.5 ml) were stirred at 130xc2x0 under N2 for several hours. The reaction was partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (30 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3xc3x9730 ml). The combined organic extracts were washed with brine (10 ml), dried (MgSO4) and evaporated in vacuo to afford a dark oil. Chromatography (SiO2; 3% MeOH/DCM) gave the title compound as a dull orange foam (360 mg, 42%). xcex4H (CDCl3) 9.19 (1H, s), 8.67 (1H, d, J 5.9 Hz), 8.24 (1H, d, J 5.8 Hz), 7.66 (1H, d, J 5.9 Hz), 7.65 (2H, d, J 8.5 Hz), 7.21 (1H, d, J 5.8 Hz), 7.16 (2H, d, J 8.5 Hz), 7.15 (1H, obscured s), 5.05-4.97 (1H, m), 4.60-4.51 (1H, m), 4.19 (2H, q, J 7.1 Hz), 3.17-3.04 (2H, m), 1.44 (9H, s), 1.27 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 459 (MNa+), 437 (MH+).
Intermediate 6 (360 mg) was treated with a solution of trifluoroacetic acid (10 ml) and DCM (10 ml) and stirred at RT for 2 h. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO3 (30 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3xc3x9730 ml). The combined organic extracts were dried (MgSO4) and evaporated in vacuo to afford the title compound as a dark orange viscous oil (280 mg, 100%). xcex4H (CDCl3) 9.18 (1H, s), 8.66 (1H, d, J 5.9 Hz), 8.22 (1H, d, J 5.8 Hz), 7.67 (1H, d, J 5.9 Hz), 7.64 (2H, d, J 8.5 Hz), 7.22 (2H, d, J 8.5 Hz), 7.19 (1H, d, J 5.8 Hz), 4.20 (2H, q, J 7.1 Hz), 3.73 (1H, dd, J 7.9, 5.1 Hz), 3.10 (1H, dd, J 13.6, 5.2 Hz), 2.87 (1H, dd, J 13.6, 7.9 Hz), 1.70 (3H, br s), 1.28 (3H, t, 7.1 Hz); m/z (ES+, 70V) 337 (MH+).
To N-(t-butyloxycarbonyl)tyrosine methyl ester (1.42 g, 4.82 mmol) in dry DMF (10 ml) was added 1-chloro-2,6 naphthyridine (0.79 g, 4.82 mmol) and cesium carbonate (1.65 g, 5.06 mmol) and the reaction stirred at 45xc2x0 under N2 for 2 days. The DMF was evaporated, EtOAc added and washed (3xc3x97) with water, dried (MgSO4), and evaporated in vacuo. The residue was chromatographed (SiO2; 40 to 100% EtOAc/isohexane) to afford the title compound as white foam (1.61 g, 82%). xcex4H (CDCl3) 9.29 (1H, s), 8.76 (1H, d, J 5.74 HZ), 8.17 (1H, d, J 5.74 Hz), 8.11 (1H, d, J 5.8 Hz), 7.43 (1H, d, J 5.8 Hz), 7.22-7.18 (3H, m), 5.03 (1H, br s), 4.61 (1H, br s), 3.75 (3H, s), 3.15-3.05 (2H, m), 1.44 (9H, s); m/z (ES+, 70V) MH+424.
A stirred solution of ethyl (S)-3-(4-aminophenyl)-2-(N-t-butyloxycarbonylamino)propanoate (3.08 g, 10.0 mmol), 1-chloroisoquinoline (1.80 g, 11.0 mmol) and N,N-diisopropylethylamine (1.42 g, 1.91 ml, 11.0 mmol) in 2-ethoxyethanol (1.0 ml) was heated at 130xc2x0 for 4 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (120 ml) and saturated aqueous NaHCO3 (50 ml). The phases were separated and the aqueous layer was re-extracted with EtOAc (80 ml). The combined organic extracts were washed with brine (30 ml), dried (MgSO4) and evaporated in vacuo. The obtained dark oil was chromatographed (silica; 20-30% EtOAc/hexane) to afford the title compound as a pink oil which crystallised on standing (2.78 g, 64%). xcex4H (CDCl3) 8.07 (1H, d, J 5.8 Hz), 7.93 (1H, d, J 8.4 Hz), 7.72 (1H, d, J 7.5 Hz), 7.63 (1H, d), 7.61 (2H, d, J 8.5 Hz), 7.51 (1H, t, J 6.8 Hz), 7.23 (1H, br s), 7.10 (1H, br s), 7.10 (2H, d, J 6.8 Hz), 5.02 (1H, br d, J 8.0 Hz), 4.54 (1H, br m), 4.16 (2H, t, J 7.1 Hz), 3.05 (2H, br m), 1.43 (9H, s), 1.25 (3H, t, J 7.1 Hz); m/z (ES+, 60V) 436 (MH+).
A stirred solution of Intermediate 9 (2.70 g) in EtOAc (100 ml) was treated with HCl gas until turbidity and precipitation was seen to occur. The reaction mixture was stirred at ambient temperatue for an addition 0.5 h. The reaction was purged with nitrogen then diluted with EtOAc (50 ml) and saturated aqueous NaHCO3 (50 ml). Sufficient solid NaHCO3 was added to ensure full neutrality. The phases were separated and the aqueous layer re-extracted with EtOAc (2xc3x9740 ml). The combined organic extracts were washed with brine (20 ml), dried (MgSO4) and evaporated in vacuo to afford the title compound as a light orange oil (2.10 g, q). xcex4H (CDCl3) 8.06 (1H, d, J 5.8 Hz), 7.91 (1H, d, J 8.3 Hz), 7.71 (1H, d, J 7.9 Hz), 7.63 (1H, obs. signal), 7.59 (2H, d, J 8.4 Hz), 7.49 (1H, app.t, J 7.8 HZ), 7.25 (1H, br s), 7.15 (1H, d, J 8.4 Hz), 7.09 (1H, d, J 5.8 Hz), 4.17 (2H, q, J 7.2 Hz), 3.68 (1H, dd, J 7.7, 5.1 Hz), 3.06 (1H, dd, J 14.6, 5.1 Hz), 2.81 (1H, dd, J 13.6, 7.9 Hz), 1.58 (2H, br s), 1.26 (3H, t, J 7.0 Hz); m/z (ES+, 60V) 435.9 (MH+).
Ethyl 4-aminocinnamate (2.5 g, 13.1 mmol) was dissolved in THF (25 ml) and treated with di-tert-butyl dicarbonate (3.14 g). The solution was refluxed for 16 h and then allowed to cool. The product was extracted into EtOAc and washed with water and brine, dried over Na2SO4, filtered and the solvent removed. The crude product was purified by column chromatography (SiO2; EtOAc/hexane 1:9) to give the title compound (2.82 g, 74%) as a white solid. xcex4H (CDCl3)7.62 (1H, d, J 16.0 Hz), 7.45 (2H, d, J 8.8 Hz), 7.38 (2H, d, J 8.8 Hz), 6.63 (1H, br s), 6.33 (1H, d, J 16.0 Hz), 4.12 (2H, q, J 7.1 Hz), 1.52 (9H, s), 1.25 (3H, t, J 7.1 Hz). m/z (ES+, 70V) 314 (MNa+).
Intermediate 11 (1.0 g, 3.44 mmol) was dissolved in THF (25 ml), treated with sodium hydride and left to stir for 20 mins. (R)-(+)-N-Benzyl(methylbenzylamine (1.44 ml) in THF (25 ml) at 0xc2x0 was treated with n-butyllithium (2.75 ml, 2.5M in hexanes) and the purple solution left to stir for 20 mins then cooled to xe2x88x9278xc2x0 and the ester anion added slowly. The reaction mixture was stirred at xe2x88x9278xc2x0 C. for 4 h then quenched with ammonium chloride solution, extracted into EtOAc, washed with water and brine, dried (Na2SO4), filtered and the solvent removed. The crude product was purified by column chromatography (SiO2; CH2Cl2) to give the tile compound (1.14 g, 66%) as a white solid. xcex4H (CDCl3) 7.42-7.17 (14H, m), 6.45 (1H, br s), 4.39 (1H, dd, J 9.4, 5.5 Hz), 3.99 (1H, q, J 6.9 Hz), 3.93 (2H, qd, J 7.1, 2.4 Hz), 3.72 (1H, d, J 14.7 Hz), 3.64 (1H, d, J 14.7 Hz), 2.63 (1H, dd, J 14.7, 5.5 Hz), 2.52 (1H, dd, J 14.7, 9.5 Hz), 1.52 (9H, s), 1.22 (3H, d, J 6.9 Hz), 1.06 (3H, t, J 7.1 Hz). m/z (ES+, 70V) 503 (MH+).
Intermediate 12 (312 mg, 0.62 mmol) in MeOH (5 ml) was treated with formic acid (0.1 ml) and 10% palladium on carbon. The reaction mixture was heated to reflux for 30 mins then cooled, filtered through celite(trademark) and the solvent removed to give the title compound (195 mg, 100%) as an oil. xcex4H (CDCl3) 8.05 (2H, br s), 7.28 (2H, d, J 8.5 Hz), 7.21 (2H, d, J 8.5 Hz,), 6.92 (1H, br s), 4.48 (1H, dd, J 8.4, 5.7 Hz), 4.05 (2H, q, J 7.1 Hz), 3.6 (1H, dd, J 17.2, 8.4 Hz), 2.79 (1H, dd, J 17.2, 5.7 Hz), 1.44 (9H, s), 1.14 (3H, t, J 7.1 Hz). m/z (ES+, 70V) 331 (MNa+).
Methyl (3R)-(3-amino)-3-(4-hydroxyphenyl)propanoate [S. G. Davies and O. Ichihara, Tetrahedron Asymmetry, (1991), 2, 183-186] (346 mg, 1.78 mmol) was dissolved in dioxan (5 ml) and sodium bicarbonate solution (5 ml) added. The solution was treated with di-tert-butyl dicarbonate (407 mg, 1.86 mmol) and stirred vigourously for 16 h. The solution was diluted with water, and the product extracted into EtOAc (xc3x972), washed with water, brine, dried (Na2SO4), filtered and the solvent removed. The product was purified by column chromatography (SiO2; CH2Cl2/MeOH 20:1) to give the title compound (211 mg, 42%) as a white solid. xcex4H (CDCl3) 7.06 (2H, d, J 8.6 Hz), 6.66 (2H, d, J 8.6 Hz), 5.48 (1H, br), 4.98 (2H, br m), 3.61 (3H, s), 2.78 (2H, m), 1.42 (9H, s). m/z (ES+, 70V) 318 (MNa+).
Intermediate 14 (420 mg, 1.42 mmol) in DMF (4 ml) was treated with potassium carbonate (394 mg) and 4-chloro-6,7-dimethoxyquinazoline (320 mg). The solution was stirred for 48 h and then water (20 ml) was added. The mixture was extracted with EtOAc (xc3x972), washed with water (xc3x973), brine, dried (Na2SO4), filtered and the solvent removed to give the title compound (657 mg, 96%) as a foamy yellow solid. xcex4H (DMSO d6) 8.53 (1H, s), 7.53 (1H, s), 7.40 (2H, d, J 8.6 Hz), 7.37 (1H, s), 7.24 (2H, d, J 8.6 Hz), 4.96 (1H, m, CH), 3.98 (3H, s), 3.95 (3H, s), 3.57 (3H, s), 2.77 (2H, m), 1.36 (9H, s). m/z (ES+, 70V) 484 (MH+).
Intermediate 15 (650 mg, 1.35 mmol) was dissolved in EtOAc (10 ml) and HCl gas was bubbled through. The reaction mixture was stirred for 2 h and the solvent removed to give the title compound (589 mg, 100%) as an oil. xcex4H (DMSO d6) 8.66 (1H, s), 7.65 (2H, d, J 8.7 Hz), 7.58 (1H, s), 7.44 (1H, s), 7.39 (2H, d, J 8.7 Hz), 3.99 (3H, s), 3.97 (3H, s), 3.58 (3H, s), 3.22 (1H, dd, J 16.3, 6.1 Hz), 3.05 (1H, dd, J 16.3, 8.5 Hz). m/z (ES+, 70V) 384 (MH+).
Methyl (2S)-[2-(tert-butoxycarbonyl)amino]-3-(4-aminophenyl)propanoate (500 mg, 1.7 mmol) and 4-chloro-2-phenylquinazoline (408 mg) were dissolved in 2-ethoxyethanol (5 ml) with Hunigs base (0.6 ml) and the solution heated at 120xc2x0 C. for 16 h. The solution was cooled and concentrated. The residue was purified by column chromatography (SiO2; CH2Cl2/MeOH 25:1) to give the title compound (682 mg, 81%) as a brown foamy solid. xcex4H (CDCl3) 8.56 (2H, dd, J 7.5, 3.7 Hz), 8.10 (1H, m), 7.95 (1H, m), 7.88 (2H, d, J 8.5 Hz), 7.80 (1H, m), 7.70 (1H, m), 7.50 (3H, m), 7.23 (2H, d, J 8.5 Hz), 5.05 (1H, m), 4.65 (1H, m), 3.72 (3H, s), 3.49 (1H, m), 3.15 (2H, m), 1.45 (9H, s). m/z (ES+, 70V) 499 (MH+).
Intermediate 17 (678 mg, 1.36 mmol) in EtOAc (30 ml) was saturated with HCl gas and stirred for 45 mins. The brown precipitate was filtered off and dried to give the title compound (518 mg, 96%) as a brown foamy solid. xcex4H (DMSO d6) 9.12 (1H, d, J 8.6 Hz), 8.83 (2H, m), 8.50 (1H, d, J 8.1 Hz), 8.44 (2H, d, J 7.1 Hz), 8.14 (1H, d, J 8.1 Hz), 8.10 (1H, t, J 8.1 Hz), 7.84 (2H, d, J 8.6 Hz), 7.70 (1H, d, J 7.1 Hz), 7.63 (2H, t, J 7.1 Hz), 7.40 (2H, d, J 8.5 Hz), 3.70 (3H, s), 3.67 (1H, m), 3.30 (1H, dd, J 14.0, 5.5 Hz), 3.18 (1H, dd, J 14.0, 7.4 Hz). m/z (ES+, 70V) 399 (MH+).
Ethyl (3R)-3{-Benzyl[(1S)-1-phenylethyl]amino}-3-[4-(tert-butoxycarbonyl)amino phenyl]propanoate (1.18 g, 2.35 mmol) was dissolved in MeOH (10 ml) and formic acid (1 ml) and 10% palladium on carbon added and the mixture refluxed for 2 h. The reaction mixture was cooled, filtered through Celite(copyright) and concentrated to give the crude title compound which was used immediately in the next reaction. xcex4H (CDCl3) 7.34 (2H, d, J 8.1 Hz), 7.27 (2H, d, J 8.1 Hz), 7.10 (1H, br s), 4.59 (1H, m), 4.11 (2H, q, J 7.1 Hz), 3.14 (1H, dd, J 16.8, 7.9 Hz), 2.86 (1H, dd, J 16.8, 12.0 Hz), 1.20 (3H, t, J 7.1 Hz).
Intermediate 19 was dissolved in EtOAc (25 ml) and the solution saturated with HCl gas. The solution was stirred at RT for 90 mins whilst a white precipitate formed. The solid was filtered and dried to give the title compound (570 mg, 88% over 2 steps) as a white solid. xcex4H (DMSO d6) 8.79 (2H, br s), 7.63 (2H, d, J 8.4 Hz), 7.36 (2H, d, J 8.4 Hz, 4.58 (1H, m), 3.98 (2H, q, J 7.1 Hz), 3.19 (1H, dd, J 16.3, 5.6 Hz), 2.99 (1H, dd, J 16.3, 9.1 Hz), 1.08 (3H, t, J 7.1 Hz). m/z (ES+, 70V) 192 (Mxe2x88x92NH3).
Intermediate 20 (550 mg, 1.96 mmol) was dissolved in dioxan (10 ml) and treated with sodium bicarbonate (1 g), water (10 ml) and di-tert-butyl dicarbonate (427 mg) and the mixture stirred for 16 h. Water was added and the product extracted into EtOAc (xc3x972), washed with brine, dried (Na2SO4), filtered and concentrated to give the crude product which was purified by column chromatography (SiO2; CH2Cl2/MeOH 20:1) to give the title compound (296 mg, 49%) as an oil. xcex4H (CDCl3) 7.07 (2H, d, J 8.3 Hz), 6.64 (2H, d, J 8.3 Hz), 5.28 (1H, br s), 4.99 (1H, m), 4.05 (2H, q, J 7.1 Hz), 2.82 (1H, dd, J 15.1, 6.5 Hz), 2.73 (1H, dd, J 15.1, 6.5 Hz), 1.42 (9H, s), 1.17 (3H, t, J 7.1 Hz). m/z (ES+, 70V) 331 (MNa+).
Intermediate 21 (250 mg, 0.81 mmol) in 2-ethoxyethanol (2 ml) was treated with 1-chloro-2,6-naphthyridine (134 mg) and heated at 120xc2x0 for 15 mins, then 100xc2x0 C. for 1 h, then cooled and concentrated. The residue was extracted into EtOAc (xc3x973), washed with sodium bicarbonate solution, brine, dried (Na2SO4), filtered and concentrated to give the crude product. The products were purified by column chromatography (SiO2; CH2Cl2/MeOH 50:1-20:1-10:1) to give the deprotected compound (106 mg, 30%) as a brown gum and the title compound (98 mg, 36%) as a yellow gum. xcex4H (CDCl3) 9.18 (1H, s), 8.66 (1H, d, J 5.9 Hz), 8.20 (1H, d, J 5.8 Hz), 7.73 (1H, d, J 5.9 Hz), 7.65 (2H, d, J 8.5 Hz), 7.30 (2H, d, J 8.5 Hz), 7.19 (1H, d, J 5.8 Hz), 5.47 (1H, m), 5.08 (1H, m), 4.09 (2H, q, J 7.1 Hz), 2.83 (2H, t, J 6.4 Hz), 1.44 (9H, s), 1.20 (3H, t, J 7.1 Hz). m/z (ES+, 70V) 437 (MH+).
Intermediate 22 (100 mg, 1 mmol) was dissolved in EtOAc (5 ml) and saturated with HCl gas. The reaction mixture was stirred to give a precipitate which was filtered and dried to give the title compound which was combined with the material isolated from the previous reaction. xcex4H (CDCl3) 9.18 (1H, s), 8.65 (1H, d, J 5.9 Hz), 7.65 (2H, d, J 8.5 Hz,), 7.37 (2H, d, J 8.5 Hz), 7.19 (1H, d, J 5.7 Hz), 4.44 (1H, t, J 6.8 Hz), 4.15 (2H, q, J 7.1 Hz), 2.68 (2H, d, J 6.8 Hz), 1.25 (3H, t, J 7.1 Hz).
A solution of N-BOC-L-tyrosine methyl ester (3.0 g, 10.2 mmol) in DMF (5 ml) was added to a suspension of NaH (60% in oil, 11.2 mmol, 447 mg) in DMF (10 ml). After 10 min, a solution of 2-chloropyrimidine (11.2 mmol, 1.28 g) in DMF (3 ml) was added and the mixture stirred overnight. The reaction was quenched with water, diluted EtOAc and washed with water and brine. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography [SiO2, EtOAc/hexane, 1:1] gave the title compound. xcex4H (DMSO d6) 8.62 (2H, d, J 4.8 Hz), 7.37 (1H, d, J 8.1 Hz), 7.28 (2H, d, J 8.4 Hz), 7.24 (1H, t, J 4.8 Hz), 7.09 (2H, d, J 8.4 Hz), 4.18 (1H, m), 3.01 (1H, dd, J 13.8, 4.6 Hz), 1.33 (9H, s).
Removal of BOC group from Intermediate 24 (HCl/EtOAc) gave the title compound as a white solid. xcex4H (DMSO d6) 8.69 (3H, m), 8.63 (2H, d, J 4.9 Hz), 7.31-7.25 (3H, m), 7.15 (2H, d, J 8.6 Hz), 4.30 (1H, m), 3.69 (3H, s), 3.19 (1H, dd, J 14.5, 6.4 Hz), 3.12 (1H, dd, J 14.3, 7.2 Hz).
A solution of N-BOC-L-tyrosine methyl ester (2.95 g, 10 mmol) in THF (10 ml) was added to a suspension of NaH (60% in oil, 11 mmol, 440 mg) in THF (30 ml) at 0xc2x0. After 10 min, a solution of 3,5-dichloroisonicotinoyl chloride (11 mml, 2.32 g) in THF (10 ml) was added and the mixture stirred at RT for 4 h. NH4Cl (aq) was added and the mixture extracted with DCM. The DCM extracts were dried (Na2SO4) and concentrated in vacuo. Recrystallisation (EtOAc/hexane) gave the title compound as white crystals (3.61 g, 77%). xcex4H (DMSO d6) 8.89 (2H, s), 7.39 (2H, d, J 8.5 Hz), 7.32 (1H, d, J 8.2 Hz), 7.23 (2H, d, J 8.5 Hz), 4.21 (1H, m), 3.62 (3H, s), 3.05 (1H, dd, J 13.8, 4.9 Hz), 2.89 (1H, dd, J 13.8, 10.5 Hz), 1.31 (9H). m/z (ES+, 70V) 410 (M++Na).
Intermediate 26 (3.61 g) in EtOAc (150 ml) was treated with HCl/EtOAc (3 m, 50 ml). The white precipitate produced was filtered off and dried to give the title compound as a white solid (1.93 g). xcex4H (DMSO d6) 8.90 (2H, s), 8.74 (3H, br), 7.42 (2H, d, J 8.5 Hz), 7.28 (2H, d, J 8.6 Hz), 4.31 (1H, m), 3.67 (3H, s), 3.25 (1H, dd, J 14.2, 6.0 Hz), 3.17 (1H, dd, J 14.1, 7.2 Hz). m/z (ES+, 70V) 369 (MH+).
n-BuLi (8.13 ml of a 1.6M solution in hexane, 13 mmol) was added slowly to a solution of 3,4-dimethoxy-3-cyclobutene-1,2-dione (1.42 g, 10 mmol) in THF (100 ml) at xe2x88x9278xc2x0. After 2 h, trifluoroacetic anhydride (2.12 ml, 15 mmol) was added. After a further 30 min the cold solution was poured into NH4Cl(aq) (100 ml) and EtOAc (100 ml) and stirred well. The aqueous layer was extracted with EtOAc. The organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, EtOAc/hexane, 30:70) gave the title compound as a yellow oil (803 mg, 48%). xcex4H (CDCl3) 4.42 (3H, s), 2.60 (2H, t, J 7.6 Hz), 1.71-1.61 (2H, m), 1.44-1.32 (2H, m), 0.94 (3H, t, J 7.3 Hz). m/z (ES+, 70V) 169 (MH+).
Activated manganese IV oxide (26 g) was added to a mixture of 3-methoxy-4-nitrobenzylalcohol (5.26 g, 28.7 mmol), N-(t-Butyloxycarbonyl)-xcex1-(diethylphosphono)glycine methylester (described in WO99/47547) (8.91 g, 27.4 mmol) and DBU (4.29 ml, 28.7 mmol) in DCM (150 ml) at 0xc2x0. The mixture was stirred at RT overnight then filtered. The filtrate was washed with dil. HCl, dried (Na2SO4) and evaporated in vacuo. Recrystallisation from MeOH gave the title compound as pale brown crystals (4.6 g). xcex4H (DMSO d6) 8.94 (1H, br s), 7.91 (1H, d, J 8.4 Hz), 7.56 (1H, d, J 1.5 Hz), 7.36 (1H, dd, J 8.5, 1.3 Hz), 7.12 (1H, br s), 3.92 (3H, s), 3.75 (3H, s), 1.37 (9H, s). m/z (ES+, 70V) 375 (M++Na).
A mixture of Intermediate 29 (2.30 g, 6.53 mmol) and palladium on charcoal (10% Pd on carbon, 230 mg) in MeOH (65 ml) was stirred under a hydrogen atmosphere at RT overnight. The catalyst was filtered off and the filtrate concentrated in vacuo. Recrystallisation (Et2O/hexane) gave the title compound as dark pink needles (1.62 g, 77%). xcex4H (DMSO d6) 7.12 (1H, d, J 7.9 Hz), 6.65 (1H, s), 6.51 (2H, s), 4.52 (1H, s), 4.49 (1H, s), 4.07 (1H, m), 3.72 (3H, s), 3.59 (3H, s), 2.81 (1H, dd, J 13.7, 5.4 Hz), 2.69 (1H, dd, J 13.1, 9.5 Hz), 1.32 (9H, s). m/z (ES+, 70V) 347 (MNa+).
A mixture of intermediate 30 (486 mg, 1.5 mmol), 4-chloro-6,7-dimethoxy quinazoline (337 mg, 1.5 mmol) and diisopropylethylamine (261 xcexcl, 1.5 mmol) in ethoxyethanol (1.5 ml) was heated at 120xc2x0 for 24 h. The mixture was diluted with DCM, washed with dil. HCl and water, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2: MeOH/DCM, 5:95) gave the title compound as a brown gum (720 mg, 94%). xcex4H (DMSO d6) 9.10 (1H, s, ArNH), 8.34 (1H, d, J 1.0 Hz), 7.85 (1H, d, J 1.4 Hz), 7.47-7.44 (2H, m), 7.40 (1H, d, J 8.0 Hz), 7.47-7.44 (2H, m), 7.40 (1H, d, J 8.0 Hz), 7.20 (1H, s), 7.07 (1H, s), 6.91 (1H, d, J 8.0 Hz), 4.34-4.28 (1H, m), 3.98 (3H, s), 3.98 (3H, s), 3.82 (3H, s) 3.70 (3H, s), 3.09 (1H, dd, J 13.8, 5.0 Hz), 2.95 (1H, dd, J 13.7, 10.0 Hz), 1.42 (9H, s). m/z (ES+, 70V) 573 (MH+).
Dry HCl was bubbled into a solution of Intermediate 31 (715 mg, 1.4 mmol) in EtOAc (30 ml) for a few seconds. The mixture was stirred at RT for 1 h. The precipitate was filtered off and dried to give the title compound as a brown solid (534 mg, 85%). xcex4H (DMSO d6, 370K) 8.57 (1H, s), 8.23 (1H br s), 7.43 (1H, d, J 7.9 Hz), 7.15 (1H, s), 6.95 (1H, dd, J 8.0, 1.5 Hz), 4.28 (1H, dd, J 7.1, 6.2 Hz), 4.02 (3H, s), 4.01 (2H, s), 3.82 (3H, s), 3.75 (3H, s), 3.31 (1H, dd, J 14.2, 6.1 Hz), 3.24 (1H, dd, J 14.2, 7.1 Hz). m/z (ES+, 70V) 413 (MH+).
Nitrogen was bubbled through a solution of N-BOC-L-4-iodophenylalanine methyl ester (1.50 g, 3.69 mmol) in toluene (20 ml) and triethylamine (10 ml). Bis(triphenylphosphine)palladium (II) chloride (10 mol %, 260 mg) and copper (I) iodide (20 mol %, 140 mg) were added. A solution of 2,6-dichlorophenylacetylene (949 mg, 5.55 mmol) in toluene (10 ml) was added by syringe-pump over 3 h. The mixture was stirred at RT for a further 3 h. The mixture was diluted with EtOAc, washed with dil. HCl and brine, dried (Na2SO4) and evaporated in vacuo. Column chromatography (SiO2; EtOAc/hexane, 20:80) gave the title compound as a brown gum (1.61 g, 97%). xcex4H (DMSO d6), 7.60-7.58 (2H, m), 7.51 (2H, d, J 8.1 Hz), 7.42 (1H, dd, J 8.8, 7.4 Hz), 7.33 (2H, d, J 8.1 Hz), 4.21 (1H, br m), 3.73 (3H, s), 3.04 (1H, dd, J 13.8, 5.0 Hz), 2.88 (1H, dd, J 13.7, 10.0 Hz) and 1.31 (9H, s): m/z (ES+, 70V) 470 (M++Na).
HCl gas was bubbled through a solution of the compound of Example 33 (1.6 g, 3.57 mmol) in EtOAc (70 ml) for 5 min. The mixture was stirred for 1 h at RT. The precipitate formed was filtered off and washed with ether to give the title compound as an off-white solid (1.21 g, 88%). xcex4H (DMSO d6), 8.73 (3H, br s), 7.60 (2H, d, J 8.0 Hz), 7.56 (2H, d, J 8.1 Hz), 7.44 (1H, dd, J 8.7, 7.6 Hz), 7.35 (2H, d, J 8.1 Hz), 4.30 (1H, t, J 6.6 Hz), 3.68 (3H, s), 3.25 (1H, dd, J 14.2, 6.1 Hz), 3.16 (1H, dd, J 14.0, 7.2 Hz); m/z (ES+, 70V) 348 (M++H).
6-Methylanthranilic acid (5 g, 33 mmol) and formamidine acetate (0.4 g, 41 mmol) were refluxed in 2-ethyoxyethanol (50 ml) for 16 h. On cooling the solvent was removed in vacuo, the residue slurried in diethyl ether, the solid filtered, washed with diethyl ether and dried to yield 3.6 g of the title compound. xcex4H (DMSO d6), 7.97 (1H, s), 7.60 (1H, dd, J 7.9, 7.6 Hz), 7.43 (1H, d, J 8.0 Hz), 7.21 (1H, d, J 7.3 Hz), 2.76 (3H, s); m/z (ES+70V)161 (MH+).
The compound of Intermediate 35 (4.1 g, 26 mmol) was refluxed in phosphorous oxychloride (60 ml) for 5 h. On cooling the phosphorous oxychloride was removed in vacuo and the residue quenched in ice cold saturated sodium bicarbonate. The resulting mixture was extracted with EtOAc (3xc3x9750 ml), washed with brine, dried (Mg2SO4), the solvent removed and the residue purified by column chromatography (silica 1:1 ethylacetate/isohexane) to yield the title compound as white solid. xcex4H (DMSO d6), 8.5 (1H, s), 7.7 (1H, dd) 7.8 (1H, d), 7.3 (1H, m)
Ethyl-(S)-3-(4-aminophenyl)-2-[(t-butoxycarbonyl)amino]propanoate (413 mg, 1.4 mmol) and Intermediate 36 (250 mg, 1.4 mmol) were heated at reflux in EtOH (10 ml). The solution was cooled, solvent removed in vacuo, residue stirred in EtOAc (10 ml) and sat. sodium bicarbonate (10 ml), organic layer isolated, washed with sodium bicarbonate, brine, dried (MgSO4) and the solvent removed, to yield the title compound as an off white solid (520 mg). xcex4H (CDCl3) 8.6 (1H, s), 7.8 (1H, br, s), 7.7 (1H, d, J 7.8 Hz), 7.6 (2H, m), 7.3 (1H, d, J 7.2 Hz), 7.2 (2H, d, J 8.7 Hz), 5.2 (1H, br m), 4.6 (1H, br m) 4.2 (2H, q, J 7.2 Hz), 3.15 (2H, br m), 3.1 (3H, s), 1.4 (9H, s), 1.25 (3H, t, J 7.2 Hz).
The compound of Intermediate 37 (1.1 g, 2.5 mmol) in DCM (4 ml) and trifluoroacetic acid (2 ml) was stirred for 1 h. The solution was poured onto saturated sodium bicarbonate and extracted with EtOAc (xc3x973). The extracts were washed with brine, dried (MgSO4), solvent removed in vacuo to give the title compound as yellow oil. xcex4H (CDCl3), 8.6 (1H, s), 7.8 (1H, br s), 7.7 (1H, d, J 8.4 Hz), 7.6 (3H, m), 7.3 (3H, m) 4.2 (2H, q, J 7.2 Hz), 3.7 (1H, m), 3.1 (1H, dd, J 13.6, 8.4 Hz), 3.0 (1H, s), 2.8 (1H, dd, J 13.6, 7.9 Hz), 1.3 (3H, t, J 7.2 Hz). m/z (ES+, 70V) 351 (MH+)
A mixture of 2-Bromo-4-trifluoromethoxy aniline (2.7 g, 10.6 mmol) palladium (II) acetate (360 mg,) triethylamine (9 ml) and 1,3-bis(diphenylphosphino)propane (651 mg) in anhydrous methanol (10 ml) and anhydrous dimethyl formamide (10 ml) were cooled in ice/methanol bath, and carbon monoxide gas was bubbled through for 10 min. The mixture was heated at 70xc2x0 under a partially inflated balloon of carbon monoxide for 17 h. On cooling nitrogen was bubbled through the solution to dispense excess carbon monoxide, and the mixture was poured onto water (50 ml) and EtOAc (50 ml), filtered through Celite(copyright), the organic layer isolated, and aqueous phase was extracted with EtOAc. The organic layers were combined, washed with water (xc3x972), brine (xc3x972), dried (MgSO4), and the solvent removed in vacuo. The residue was distilled and the fraction boiling at 170xc2x0, 0.08 mbar collected to yield 1.8 g of a yellow liquid. xcex4H (CDCl3), 7.7 (1H, m), 7.1 (1H, m), 6.6 (1H, d, J 9.0 Hz), 3.9 (3H, s).
Prepared in a similar manner to the compound of intermediate 35 from the compound of Intermediate 39. xcex4H (DMSO d6), 8.1 (1H, s), 7.9 (1H, s), 7.8 (2H, m).
Prepared from the compound of Intermediate 40 in a similar manner to that described for Intermediate 36. xcex4H (CDCl3), 9.1 (1H, s), 8.1 (1H, d, J 9.2 Hz), 80 (1H, m), 7.8 (1H, m); m/z (EI+, 70V) 249/251.
Prepared from Intermediate 41 in a similar manner to that described for Intermediate 37. xcex4H (CDCl3), 8.7 (1H, s), 8.0 (1H, d, J 9.1 Hz), 7.8 (1H, br s), 7.6 (3H, m), 7.2 (2H, d, J 8.5 Hz), 5.0 (1H, br s) 4.5 (1H, br s), 4.2 (2H, q, J 7.2 Hz), 3.1 (2H, br s), 1.4 (9H, s), 1.2 (3H, t, J 7.2 Hz).
Prepared from the compound of Intermediate 42 in a similar manner to that described for Intermediate 38. xcex4H (CDCl3), 8.7 (1H, s), 7.9 (1H, d, J 9.2 Hz), 7.7 (1H, br m), 7.6 (3H, m), 7.2 (2H, d, J 7.1 Hz), 4.2 (2H, q, J 7.2 Hz), 3.8 (1H, m), 3.1 (1H, m), 2.9 (1H, m), 1.3 (3H, t, J 7.2 Hz); m/z (El+, 70V) 421 (MH+)
3,4-Dimethoxy-3-cyclobutene-1,2-dione (1.3 g, 9.2 mmol) in of MeOH (10.0 ml) was treated with aqueous ammonia (10.0 ml of a 2.0M solution) and stirred at ambient temperature for 2 h. The yellow precipitate thus formed was recovered by filtration, washed with MeOH and Et2O and dried in vacuo to afford the title compound (0.87 g, 75%) as an amorphous yellow powder xcex4H (d6 DMSO) 8.32 (2H, br s), 4.28 (3H, s). m/z (ES+, 70V) 127 (MH+).
Prepared in a similar manner to the compound of Intermediate 9 from methyl-(S)-3-(4-aminophenyl)-2-(N-t-butoxycarbonylamino)propanoate and 2,4-dichloro-6,7-dimethoxyquinazoline. xcex4H (CD3OD) 7.72 (1H, s), 7.69 (2H, d, J 8.4 Hz), 7.25 (2H, d, J 8.4 Hz), 7.05 (1H, s), 4.34 (1H, m), 4.15 (2H, m, J 7.1 Hz), 4.00 (3H, s), 3.96 (3H, s), 3.08 (1H, m), 2.97 (1H, m), 1.40 (9H, s), 1.23 (3H, t, J 7.1 Hz). m/z (ESI+ 531 (MH+).